Toll-Like Receptor-7 Signaling Promotes Nonalcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice

Abstract

Toll-like receptor 7 (TLR7) signaling regulates the production of type 1 interferons (IFNs) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, implicated in the control of regulatory T (Treg) cell activity. However, the mechanistic interplay between TLR7 signaling and Treg cells in nonalcoholic steatohepatitis (NASH) has not been elucidated. Our aim was to clarify the role of TLR7 signaling in the pathogenesis of NASH. Steatohepatitis was induced in wild-type (WT), TLR7-deficient, IFN-α/β receptor 1-deficient, and Treg cell-depleted mice. TLR7-deficient and IFN-α/β receptor 1-deficient mice were more protective to steatohepatitis than WT mice. Of interest, both TNF-α and type 1 IFN promoted apoptosis of Treg cells involved in the prevention of NASH. Indeed, Treg cell-depleted mice had aggravated steatohepatitis compared with WT mice. Finally, treatment with immunoregulatory sequence 661, an antagonist of TLR7, efficiently ameliorated NASH in vivo. These results demonstrate that TLR7 signaling can induce TNF-α production in Kupffer cells and type I IFN production in dendritic cells. These cytokines subsequently induce hepatocyte death and inhibit Treg cells activities, leading to the progression of NASH. Thus, manipulating the TLR7-Treg cell axis might be used as a novel therapeutic strategy to treat NASH.

Ferroptosis Affects the Progression of Nonalcoholic Steatohepatitis via the Modulation of Lipid Peroxidation–Mediated Cell Death in Mice

“…To establish an in vitro NASH model, primary HPs were treated with 0.4 mmol/L PA, as previously described. 21 Stock solutions of RSL-3, Lip-1, and SS were prepared and stored at À20 C. DFO was freshly prepared and dissolved in culture medium. Primary HPs were treated with the indicated concentration of these compounds.…”

Immunological mechanisms and therapeutic targets of fatty liver diseases

“…Toll-like receptor-7 signaling promotes NASH by inhibiting regulatory T cells in mice. 253 Memory CD4 + and CD8 + Tcell numbers are increased while naïve T-cell numbers are decreased in the peripheral blood of NAFLD patients. 254 Moreover, the number of infiltrating CD8 + T cells in the portal vein is elevated in NAFLD patients and is associated with the severity of hepatic inflammation.…”

Treatment with a Toll‐like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice

“…In an experimental study of allergy, using several knockout models the authors showed that TLR7 activation resulted in IL-10 production in splenic B cells that in turn led to T reg expansion. However, in a recent paper by Roh et al [36] an antagonist is used to block TLR7 in studies of nonalcoholic steatohepatitis (NASH) and this treatment ameliorated disease. Taken together, further studies are required to pinpoint effects of TLR7 agonists versus antagonist in the T reg compartment.…”